Journal article
Inhibition of the 26S Proteasome Induces Expression of GLCLC, the Catalytic Subunit for γ-Glutamylcysteine Synthetase
Biochemical and biophysical research communications, Vol.270(1), pp.311-317
04/02/2000
DOI: 10.1006/bbrc.2000.2419
PMID: 10733945
Abstract
The majority of short- and long-lived cellular proteins are degraded by the activities of the 26S proteasome, a large multi-catalytic protease. Its unique function places it as a central regulatory activity for many important physiological processes. Lactacystin is a very specific 26S proteasome inhibitor and represents an excellent tool for demonstrating that a pathway exhibits proteasome-dependent biochemical regulation. Exposure of HepG2 cells to lactacystin resulted in robust elevation of GLCLC mRNA levels, followed by an increase in GSH concentrations. GLCLC is the gene that encodes the catalytic subunit for γ-glutamylcysteine synthetase, the rate-limiting enzyme for the synthesis of glutathione (GSH). Inhibition of non-proteasome, protease activities did not induce GLCLC. Gel mobility shift assays and expression of CAT activity from heterologous reporter vectors identified Nrf2 mediation of the GLCLC antioxidant response element, ARE4, as the mechanism by which lactacystin induced GLCLC. These studies have identified 26S proteasome activity as a central regulatory pathway for glutathione synthesis.
Details
- Title: Subtitle
- Inhibition of the 26S Proteasome Induces Expression of GLCLC, the Catalytic Subunit for γ-Glutamylcysteine Synthetase
- Creators
- Konjeti R Sekhar - Department of Radiation Oncology and Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee, 37232Syrus R Soltaninassab - Department of Radiation Oncology and Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee, 37232Michael J Borrelli - Department of Radiation Oncology, William Beaumont Hospital, Royal Oak, Michigan, 48073Zhi-Qi Xu - Department of Radiation Oncology and Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee, 37232Michael J Meredith - Department of Oral Molecular Biology, School of Dentistry, Oregon Health Science University, Portland, Oregon, 97201Frederick E Domann - Radiation Research Laboratory, University of Iowa, Iowa City, Iowa, 52242Michael L Freeman - Department of Radiation Oncology and Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee, 37232
- Resource Type
- Journal article
- Publication Details
- Biochemical and biophysical research communications, Vol.270(1), pp.311-317
- Publisher
- Elsevier Inc
- DOI
- 10.1006/bbrc.2000.2419
- PMID
- 10733945
- ISSN
- 0006-291X
- eISSN
- 1090-2104
- Language
- English
- Date published
- 04/02/2000
- Academic Unit
- Pathology; Surgery; Radiation Oncology
- Record Identifier
- 9984047746602771
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